Mechanisms of neurodegenerative diseases are poorly understood, but accumulations of filamentous brain lesions are hallmarks of these disorders suggesting that protein misfolding, fibrillization and amyloid deposition play central roles in their onset/progression. For example, abnormal alpha-synuclein flbrillizes to form Lewy bodies (LBs) in Parkinson's disease (PD), dementia with LBs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) composed of alpha-synuclein filaments. Moreover, the convergence of abundant LBs with Abeta plaques and tau tangles in AD suggests that pathological interactions between such as alpha-synuclein, tau and Abeta account for the frequent overlap of AD and PD. Indeed, data from studies of in vitro and in vivo models of neurodegenerative synucleinopathies in this Program Project Grant (PPG), prompt us to hypothesize that fibrillization and aggregation of alpha-synuclein play mechanistic roles in neurodegenerative synucleinopathies, and that interactions of alpha-synuclein with other disease proteins such as tau, Abeta and/or DJ-1 may augment neurodegeneration while chaperones may counteract this. This PPG competing renewal application tests these hypotheses in 4 complementary Projects supported by Administrative and Neuroscience Cores. These synergistic Projects pursue research on authentic human synucleinopathy brains (Project 0007), as well as on mechanisms of neurodegenerative synucleinopathies in transgenic fly (Project 0008) and transgenic mouse (Projects 0007, 0009, and 0010) models. This newly re-configured PPG takes advantage of substantial progress from the current funding cycle to propose novel interdisciplinary studies to provide insights into mechanisms of brain degeneration in synucleinopathies and related disorders. Accomplishment of the studies proposed here will accelerate efforts to improve the diagnosis and therapy of these and other neurodegenerative disorders characterized by filamentous brain lesions.